Improved process for preparing 9alpha-fluoro-delta1, 4-3, 20-diketo-11beta, 17alpha-dihydroxy-21-acyloxy-pregnadiene



tates IMPROVED PROCESS FOR PREPARING 9u-FLU- ORO-A -3,20-DIKETO 1113,170: DIHYDROXY-21- ACYLOXY-PREGNADIENE No Drawing. Application May 26, 1955 Serial No. 511,403

6 Claims. (Cl. 260-39745) Unite This invention is concerned generally with novel processes for preparing steriod compounds. More particularly, it relates to an improved dehydrobromination method for preparing 9aluoro-A -3,ZO-diketo 1lfi,17a dihydroxy-2l-acyloxy-pregnadiene compounds from the corresponding 2,4-d1bI'OInO-9Ct-flllOIO-3,ZO-dlkCtO-l 1 3, l7a-dihydroxy-Zl-acyloxy-allopregnane. The 9a-fluoro-A -3,20- diketo-l 1fi,17u-dihydroxy 21 acyloxy-pregnadienes obtained in accordance with this improved method possess extremely high cortisone activity and, in addition, are relatively free of the sodium and water retention action characteristic of cortisone, hydrocortisone, and 9a-fluoro-hydrocortisone.

Heretofore, 9a-fluoro-A -3,ZO-diketo 115,170 dihydroxy-2l-acyloxy-pregnadienes have been prepared by reacting 2,4-dibromo-9a-fluoro-3,20-diketo-11p,17a-dihydroxy-2l-acyloxy-allopregnane with other dehydrohalogenating agents such as 2,4-dinitrop'henylhydrazine, but the dehydrobrominated products obtained by this prior method have been impure and the yields of the desired 9afluoro-A -3,2O-diketo-11,3,17a-dihydroxy 21 acyloxypregnadiene have been low.

It is now discovered that relatively high yields of 9afluoro-A -3,20-diketo-115,17a-dihydroxy 21 acyloxy pregnadienes can be obtained by dehydrobromination of a crude dibromide comprising 2,4-(iibromo-9a-fluoro-3,20- diketo-l 1 [3,17u-dll1Yd1OXY 21 acyloxy-allopregnanes providing the reaction is conducted in a medium comprising an N,N-dialky1acyl amide. This process may be chemically represented as follows:

wherein R is an acyl radical.

In carrying out this improved method, the 2,4-dibromo-9a-fluoro-3,ZO-diketo 115,170 dihydroxy-21- acyloxy-allopregnane is heated with the N,N-dialkylacylamide as for example an N,N-dialkyl-fonnamide such as dimethylformamide, diethylformamide, and the like, at an elevated temperature. The reaction is ordinarily conducted at a temperature within the range of approximately 100-150 C., although higher or lower reaction temperatures may be utilized if desired; the reaction is conveniently carried out under reflux, under which conditions the reaction is usually complete in about 1-2 hours. While the N,N-dialky1-acylamide canbe employed as the sole dehydrobrominating agent, it is preferred to employ a mixture of said N,N-dialkyl-acylamide and a tertiary keto 11fi,17a,21 trihydroxy-allopregnane amine, such as collidine, dimethylaniline, and the like;

using my preferred dehydrobromination mixture com-.

prising about five parts of dimethylformamide and two parts of collidine to one part of 2,4-dibromo-9a-fluoro- 3,20-diketo-11B,17a-dihydroxy 21 acyloxy-allopreg' acid solution and a water-immiscible organic solvent as for example a halogenated hydrocarbon solvent such as chloroform, dichloromethane, and the like; the tertiary amine and N,N-dialkyl-acylamide remain in the aqueous layer and the dehydrobrominated steroid reaction product is extracted into the halogenated hydrocarbon solvent layer, and is recovered therefrom by evaporating the solvent. The residual material thus obtained may be purified by chromatography over alumina to give the desired 9a-fluoro-A -3,ZO-diketo-l1,8,17a-dihydroxy 21 acyloxy pregnadiene compound in substantially pure form. In accordance with this method and utilizing, as the 2,4- dibromo-S a-fluoro 3,20 diketo-llB,17a-dihydroxy 21- acyloxy-allopregnane starting materials, 2,4-dibromo-9w fluoro 3,20 diketo-l1 3,17a,2l-trihydroxy-allopregnane- 21-alkanoate, 2,4-dibromo-9a-fluoro 3,20 diketo- 11e,170,21-trihydroxy-allopregnane ZI-acetate, 2,4-dibromo-9a-fluoro 3,20 diketo-l1,3,17d,21-trihydroxy-allopregnane 21-propionate, 2,4-dibromo-9a-fluoro-3,20-di- 21-benzoate,

'. and the like, there are obtained -9a-fluoro-A -3,20-diketo- 1113,17or-dihydroxy-2l-acyloxy-pregnadienes such as fiuoro-A -3,20-diketo 1l,3,17oc,21 trihydroxy-pregnadiene 21-a1kanoate, 90z-fil10IO-A r3,ZO-diketO-l1,8,170,21-

trihydroxy-pregnadiene 2l-acetate, 9or-fluoro-A -3,20-diketo-l15,17u,2l-trihydroxy-pregnadiene 21 propionate, 9oc-fillO1O-A -3,2O-(likiQ 11B,17a,21 trihydroxy-pregnadiene 21-benzoate, and the like.

The following examples illustrate methods of carry-.

ing out the present invention but it is to be understood that these examples are given for purposes of illustration. and not of limitation.

Example 1 Approximately one gram of 2,4-dibromo-9a-fluoro- 3,20 diketo 11,8,17a-dihydroxy-2l-acetoxy-allopregname is mixed with 2 cc. of collidine and 5 cc. of dimethylformamide, and the mixture is heated under reflux for a period of about minutes. The reaction mixture is cooled and distributed between dichloromethane and di lute aqueous hydrochloric acid solution. The dichloromethane layer is washed with dilute aqueous hydrochloric acid solution and then with water until neutral and free of dirnethylformamide. The washed dichloromethane layer is then evaporated in vacuo, and the residual material is purified chromatographically to give substantially pure 9a fluoro A -3,2O diketo 11p, 17oz dihydroxy- 21-acetoxy pregnadiene; M. P. 237 C.; [a] +l0O.9 in acetone.

Example 2 with dilute aqueous hydrochloric acid solution,'with 5% aqueous sodium bicarbonate solution, and then with water until neutral and free of dimethylformamide,

Patented June 3, 1958- The solvent is evaporated from the washed chloroform layer is vacuo to give6.1-9-g. of crude A -9a-fluoro-3,20- diketo 11,9,17u dihydroxy 21 acetoxy-pregnadiene. 6.15 g. of this crude A -9Ct-fillQIO-3,2O-dikt0-115,1711- dihydroxy 2l-acetoxy pregnadiene is dissolved in 135 cc. of 2 l benzene chloroform mixture, and the resulting solution passed through a column of 258 g. of neutral alumina. The resulting adsorbate is eluted with chloroform, the chloroform eluate is evaporated to dryness in vacuo, and the residual material is recrystallized from acetone to give substantially pure A '9 fiuoro-3,20- diketo '1 118,170; dihydroxy 21 acetoxy pregnadiene; M. "P. 236 C.

The 2,4-- dibromo 9a fiuoro 3,20 (lik6t0-11fl,17utdihydroxy-Zl-acetoxy-allopregnane used as starting material in Examples 1 and 2 may be prepared starting with 9m-fluoro hydrocortisone acetate (A -9a fluoro- 3,20- dike'to 115,170: dihydroxy 21 acetoxy pregnene) as follows: 12.0 g. of palladium on charcoal catalyst are added to a suspension of 14.5 g. of said A -9a-fiuoro 3,20 diketo 11,8,17a,2l-trihydroxy-pregnene Zl-acetate in 1500 cc. of methanol, and the mixture is reacted with hydrogen at atmospheric pressure while maintaining the reactants at about room temperature. The absorption of hydrogen ceases after about 15 minutes; the amount of hydrogen absorbed corresponds to one mole. The reaction mixture is filtered, thereby removing the catalyst, and the catalyst is washed thoroughly with methanol. The filtrate and washings "are combined, and the resulting solution is evaporated to dryness in vacuo. The residual material is then recrystallized twice from acetone to give about 8 grams of substantially pure 9oz fiuoro 3,20- diketo 115,17a dihydroxy 21 acetoxy-allopregnane. Eight grams of 90 fiuoro 3,20 diketo 11B,17oc-dlhydroxy -"2hacetoxy-allopreghane is dissolved in 280 cc. of glacial acetic acid, and to this solution is added 2.0 cc. of an 0.95 Nsolution of hydrogen bromide in glacial acetic acid. To this solution is added a glacial acetic acid solution containing two molecular equivalents of bromine (based on the steroid compound) and, after the uptake of bromine is complete, an additional 50 cc. of the 0195 N solution of hydrogen bromide in glacial acetic acid is added. The resulting solution is maintained at room temperature for a period of approximately 2 /2 hours, The reaction mixture is poured into water, and

the precipitated material is recovered by filtration and I claims, they are to be considered as part of our invention.

Insofar as these changes and modifications are within the purview of the annexedv We claim:

1. In the process of dehydrobrominating 2,4-dibromo- 9a fiuoro 3,20 diketo 11 3,1711 dihydroxy 21- lower alkanoyloXy-allopregnane to produce fiuoro- A -3,20 diketo 11,8,170: dihydroxy 21 lower alkanoyloxy-pregnadiene, the improvement which cornprises conducting said dehydrobromination in the presence of an N,N-diallryl-acylamide.

2. In the process of dehydrobrominating 2,4-dibromo- 9m fiuoro 3,20 dilreto 113,170: dihydroxy 2l-lower alkanoyloKy-allopregnane to produce 9a-fluoro-A -3.,20- diketo 115,170; dihydroxy 21 lower alkanoyloxy- I pregnadiene, the improvement which comprises conducting said dehydrobromination in the presence of an N,N- dialkyl-formamide.

3. In the process of dehydrobrominating 2,4 dibromo- 9a fiuoro 3,20 diketo l1fi,17u,21 trihydroxy-allopregnane 21-acetate to produce 90: fiuoro-A -3,20-diketo 11p,17u,2'1 trihydroxy-pregnadiene 21 acetate, the improvement which comprises conducting said dehydrobromination in the presence of dimethylformamide.

4. The process which comprises reacting a 2,4 dibromo 9oz fiuoro 3,20 diketo 1119,17; dihydroxy- 21-acyloxy-ailopregnane with a tertiary amine in the presence of an N,N-dialkyl-acylamide thereby forming the corresponding 90: fiuoro-M 320 diketo 115,17a dihydroxy 21 acyloxy-pregnadiene in substantially enhanced yield.

5. The process which comprises reacting 2,4 dibromo- 90c fiuoro 3,20 diketo 11B,17a,21-trihydroxy+allopregnane 2l-acetate with collidine in the presence of dimethylformamide thereby forming 9a fluoro-A -3,'20- diketo 11p,17a,21 trihydroxy-pre'gnadiene ZI-acetate in substantially enhanced yield.

6. In the process of dehydrobrominating a crude dibromide comprising 2,4 dibromo 9oz fluoro 3,201

References Cited in the file of this patent UNITED STATES PATENTS OTHER REFERENCES Fried, ,Jour. Am. Chemical Soc. 75, 2273 (1953). Fried, Jour. Am. Chemical Soc. 76, 1455-6 (1954). 

1. IN THE PROCESS OF DEHYDROBRONINATING 2,4-DIBROMO9A - FLUORO - 3,20 - DIKETO - 11B,17A - DIHYDROXY - 21 LOWER ALKANOYLOXY-ALLOPREGNANE TO PRODUCE 9A - FLUORO$1,4-3,20 - DIKETO - 11B, 17A - DIHYDROXY - 21 - LOWER ALKANOYLOXY-PREGNADIENE, THE IMPROVEMENT WHICH COMPRISES CONDUCTING SAID DEHYDROBROMINATION IN THE PRESENCE OF AN N,N-DIALKYL-ACYLAMIDE. 